This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sexual transmission of human immunodeficiency virus (HIV) accounts for the majority of new infections worldwide. A vaccine capable of preventing sexual transmission across genital or rectal mucosal surfaces could provide a method for stopping the AIDS epidemic. The ultimate success of strategies to prevent sexual transmission of HIV depends, in part, on a better understanding of the virological and immunological mechanisms that underlie sexual transmission. Numerous studies have demonstrated the difficulty to achieve sterile protection from vaginally or rectally acquired HIV/SIV using parenteral immunization. Mucosal immunization is seen as the best approach to achieve sustainable immune responses at mucosal sites of viral entry. Defining the mechanisms of vaginal HIV transmission, in particular the initial immune response is central to the development of effective strategies to develop a successful mucosal AIDS vaccine. Our knowledge of the initial target cells involved in mucosal transmission is still evolving. Increasing evidence suggests that the initial site of productive infection occurs in situ at the mucosal surface. Studies of vaginal transmission suggest that the potential initial target cell may be either activated CD4+ T cells or intraepithelial dendritic cells. Precise dissection of viral targets and pathways involved in sexual HIV transmission will prove essential to the global effort to develop a protective vaccine. The identification of initial target cells and the ability to elicit and to enhance cellular or humoral immune responses at mucosal sites is likely to be a crucial step in the development of novel vaccines. These questions are extremely difficult to pursue experimentally in humans. In this study we propose to examine in situ viral infection at mucosal portal of entry in the SIV/cynomolgus (Macaca fascicularis) macaque model using SIV tagged with GFP. Specific aims will include: 1) To identify the types of cells initially infected (i.e., lymphocytes, macrophages, and dendritic cells), their phenotype and function;2) To investigate the mechanisms, time course, and pathways of viral spread from site of initial infection;and, 3) To explore generation of early mucosal cellular immune response at vaginal site of SIV infection.